Susan B. Horwitz, PhD

2008-2009 BCRF Project:
Co-investigator: Hayley M. McDaid, PhD, Albert Einstein College of Medicine, New York, NY

Over the past year, Drs. Horwitz and McDaid have focused on generating Taxol–resistant cells, taking a unique approach that differs from prior strategies. They have exposed cells to Taxol in a manner that mimics the way patients are administered the drug. The data that is generated from analysis of these resistant lines will be more applicable to human breast tumors that have acquired resistance to Taxol. The researchers are studying the expression of DNA in Taxol-resistant breast cancer and have found genes that are inappropriately switched off and on in these cells, through what are called epigenetic mechanisms, utilizing novel methods developed at Albert Einstein College of Medicine.

They will expand on these studies by investigating another mechanism by which genes can be switched off and on in cells that are Taxol-resistant. This may be mediated by the action of microRNAs, which are small pieces of RNA that prevent functional proteins from being made in cells. As many as 30% of human genes are predicted to be regulated by miRNAs and Drs. Horwitz and McDaid will use specific technology to determine which microRNAs are involved in Taxol-resistance in breast cancer. Their results will lead to an in-depth understanding of Taxol-resistance that is necessary for strategies to overcome the problem of drug-resistance.

Mid-year Progress Report:
Taxol is an important drug for the treatment of breast cancer. However many human tumors are inherently resistant to the drug or acquire resistance during treatment. Drs. Horwitz and McDaid are studying the expression of genes in Taxol-resistant breast cancer and have found ones that are inappropriately switched off and on in these cells. They are utilizing novel methods developed at Albert Einstein College of Medicine to help identify these genes.

During the past four months, they have expanded on these studies by investigating a second mechanism by which genes can be switched off and on in cells that are Taxol-resistant. This mechanism is mediated by the action of microRNAs, which are small pieces of RNA that prevent protein synthesis by inhibiting protein translation or by leading to mRNA degradation. As many as 30% of human genes are predicted to be regulated by miRNAs and the researchers have successfully utilized miRNA microarray analysis to identify miRNAs that are differentially expressed in drug resistant compared to the corresponding drug-sensitive cells. Their data indicate that miRNAs play an important role in drug resistance.

They are in the process of validating our data by a second method. They will spend the remaining eight months of this funding term analyzing miRNA expression in the two MCF-7 Taxol-resistant breast cell lines they have generated during the first year of this grant. They are also expanding these studies to include a clinically-derived Taxol-resistant breast cancer model, pat-21, which was derived from a patient with intrinsic resistance to Taxol. These studies will generate an miRNA signature for both intrinsic and acquired resistance to Taxol that will be used to devise diagnostic and therapeutic strategies for breast cancer treatment.

Bio:
Dr. Susan Band Horwitz is a Distinguished University Professor at the Albert Einstein College of Medicine and Associate Director for Therapeutics at the Albert Einstein Cancer Center. She grew up in Boston and after graduating from Bryn Mawr College, received her Ph.D in Biochemistry at Brandeis University.

Dr. Horwitz has had a continuing interest in natural products as a source of new drugs for the treatment of cancer. Her laboratory has made Taxol, a drug isolated from the yew plant, Taxus brevifolia, a major focus of its work. Although no one was interested in Taxol when she began her studies, today it is an important anti-tumor drug that has been given to over a million patients. Dr. Horwitz' research played an important role in encouraging the development of Taxol by the National Cancer Institute.

Dr. Horwitz and her collaborators demonstrated that the effects of Taxol were due to a novel interaction between the drug and microtubules, the latter being essential for the pairing and segregation of chromosomes during cell division. Her pioneering investigations and perceptive analysis of the results identified Taxol as a prototype of a new class of anti-tumor drugs. Extensive research has led to major insights into several aspects of the chemistry and biology of Taxol. Dr. Horwitz also has made significant contributions to our understanding of the molecular mechanisms underlying Taxol resistance in tumor cells.